3, 6-diamino-n-(substituted)pyrido[2, 3-b]-pyrazine-2-carboxamides



United States Patent 3,180,868 3,6-DIAMINO-N-(SUBSTITUTED)PYRIDO[2,3-b]- PYRAZINE-Z-CARBOXAMIDES Thomas S. Osdeue, Berwyn, and Arthur A. Santilli, Ardmore, Pa., assignors to American Home Products Corporation, New York, N .Y., a corporation of Delaware No Drawing. Filed July 24, 1963, Ser. No. 297,231 Claims. (Cl. 260-250) 1-0 0 2 EN \N -NH2 wherein R represents hydrogen or a lower alkyl group having up to 2 carbon atoms; R and R represent lower alkyl groups having up to 5 carbon atoms, and when taken together to form .a closed ring, represent a morpholino, piperidino or pyrrolidino radical; Alk represents a lower alkyl group having up to 4 carbon atoms and the letter n is an integer ranging (from 2 to 4.

The compounds of this invention are prepared by reacting in an anhydrous alcohol such as ethanol,.or 2-ethoxy-ethanol, in the presence of a basic catalyst, preferably sodium metal, 2,6diamino-3-nitrosopyridine with a 2- cyano-N-(tert-aminoalkyl)acetamide, a Z-cyano-N-alkyl- Ndtert-aminoallcyl)acetamide or with a Z-cyano-N-(oxyalkyl)acetamide, a 2cyano-=N-alkyl-N-(oxyalkyl)acetamide or with a 2-cyano-rN-(alkylthioalkyl)acetamide or its N-alkyl derivative in which the alkyl moieties are as defined above for the final products. These starting acetamides are prepared by treating ethyl cyanoacetate with the appropriate amine with or without a solvent.

In preparing the compounds of this invention, the abovenamed reactants are refluxed and agitated for a period of time of about four hours. The reaction mass is then concentrated to precipitate the desired product which is removed and recrystallized from ethanol or aqueous ethanol.

The invention will be more fully set forth in the following more detailed description which includes examples that are given as illustrative embodiments of the invention and not as limitations thereof.

\Example 1 To a solution of 0.2 grof sodium in absolute ethanol was added 6.9 g. of .2, 6-diamino-S-nitrosopyridine and 10 g. of 2-c'yano-N- (Z-diethylaminoethyl)acetamide. The

3,180,868 Patented Apr. 27, 1955 ice mixture was stirred and boiled under reflux for 4 hrs., and was then concentrated to a volume of 200 ml. ona rotary evaporator. After cooling, the yellow precipitate which 'had formed was removed by filtration. Recrystallization [from ethanol afforded 3,-6-diamino-N-(2-dietl1ylaminoethyl)pyrido[2,3 b] pyrazine-Z-carboxamide, M.P. 2164217, wt.=8.45 .g.

Analysis-flalculated: (3:55.43, H=6.98, N=32.32. Found: (1:55.28, I'IZ6J74, N=3-2.=3-3.

When tested pharmacologically by the Agar Serial Dilution Technique, this compound exhibited activity against Bacillus subtilis 6633 and SR, S. aureus, Mycobacteriurn spp., Escherichia coli SR, Salmonella paratyplzi and Brucella bronchiseptica.

Example 2 To a solution of 0.5 g. of sodium in 400 ml. of dried Z-ethoxyethanol was added 9.66 g. of 2, 6diamino-3-nitrosopyridine, followed by 13.0 g. of 2-cyano-N-(3-dimethylaminopropyDacetamid-e. The mixture was stirred and boiled under reflux for 4 hrs. and then was filtered. The solvent was removed on a rotary evaporator when a brown residue was obtained, wt.=17.'5 9, M.P. 210. Recrystallization from aqueous ethanol afforded 3,6-diamino- N (S-dimethylaminopropyl)pyrido [2, 3-b]pyrazine-2-carboxamide, M.P. 209.

Analysis.-Calculated: (3:53.98, H=6.t57, N=33.9l- F-oundz C=513. 9-1, H=6. 36, N=33.9tl.

When tested for antibacterial activity by the Agar Serial Dilution Technique, this compound was active against B. subtilis 6633, S. aureus 2 09i and L. casez'. The compound also exhibited diuretic activity.

Example 3 To a solution of 0.2 g. of sodium in .200 ml. of absolute ethanol was added 4.14 g. of 2,6-diamino-3-nitrosopyridine, followed by 5415 g. of Z-cyano-N (2-ethoxyethyl)- acetamide. The mixture was stirred and boiledunder retlux for 0. hrs. On cooling a yellow precipitate was obtained which was removed by filtration, wt.=7.4 g., M.P. 212. 'Recrystallidation from ethanol afforded 3,6-diamino N (Z-ethoxyethyl)pyrido[2,3-b]pyrazine 2-carboxamide, M.P. 2L6;

Analysis.Calculated: C=52.1'6, H=5.84, N=30.42. Found: 'C=51.89, H=5.67, N=30.41.

When tested pharmacologically, this compound exhibited anti-inflammatory activity.

Example 4 To a solution of 0.97 g. of sodium in 200 m1. of absolute ethanol was added 4.96 g. of 2,6-diarnino-3-nitrosopyridine, followed by 5.4 g. of 2-cyano-N-(2-hydroxy n it Name of product 2-cyano-N-(2-dimethylsininoethyl) aeetamide.

2-cyano N-(4-othoxybutyl)acetamide.

Z-cyano-N-(Z-methoxyethyl) acetamide.

Z-cyano-N-(3-isopropoxypropy1) acetemide.

2-eynno-N-(fl-morpholinoethyl) acetamide.

2 -cyau-N- (2-piperidionethyl) acetami e.

2-cyano-N (2-diis0propylamh10- ethyl) acetamide.

2-cyano-N-methyl-N-(Z-dimethylamiuoethyDacetamide.

2-cyan o-N-(3-diethylamincpropyl) acetamide.

Q-cyauo-N-(2-;iimethylaminopropyl)acetounde.

2-cyano-N-(3-n1orpholinopropyl) aeetumide.

ano-N-(2-pyrrolidinoethyl) acetamide.

2-cyano-N-(4-dimetl1ylamin0- butyl) acetamide.

2-cyan0-N-etl1yl-N-(Z-dimethylamiuoethybacotamide.

Z-eyano-N-(S-methoxypropyl) acetamide.

2-cyano-N-(2-ethylthioethyl) acetamide.

2-eyano-N-(tbutylthiobutyl) acetamide.

2-cyano-N-(4-butoxybutyl) acetamide.

Z-cyano-N-cthyl-N-(3-isopropoxypropyDacetamide.

Q-QyanQ-N-ethyl-(4-butylthiobutyl) acetamide.

3,(i-(iiamino-N-(2-din1ethyla1ninoethyl) pyriGOIZB-lflpyraZine-Z- oarboxamidc. 3,6-dia1nino-N-( t-ethoxyhutyl) pyrido[2,3-b]pyrszine-Z-csrboxamide. 3,6-diaininoN-(2methoxyethyl) pyrido[2,3-b1pyrazinc-2-carboxamide. 3.6diemino-N-(3-is0propyl) pyrido[2,3-b1pyrazinc-2-carboxamide. 3,6-diarninoN-(2-morpholinoethyl)pyrido[2,3-b]pyraziue-2- earboxamide. 3,6-dinmino-N-(2 piperidiuoethyl) pyrido[2,3-b1pyrazine-2-carboxamide. 3,6-dia1'nino-N-(2-(liisopropylaminoethyhpyrido [2,3-13] pyrazine-Z-carboxamide. 3,fi diamino-N-rnethyl-N-(2- dimethylaminoethyl)pyrido [2,3-b]pyrazine-2carb0xarnide. 3 G-di'n 12 diethylaminopropyl)pyrido[2,3-b]pyrazine-Z- carhoxainidc. 3,G-(linminc-N-(B-di-n-butylaminopropyl)pyrido[2,3-b] nyrazino-Z-cnrboxamido. 3,6-dian1ino-N-(Q-(limothylaminopropyl)pyrid0[2,3-b]pyrazine-Q- cnrboxnniido. 3,6-diamino-N-(3-morpholinopropyl)pyrido[2,3-b]pyrezine2- carboxarnide. 3,6-dian1ino-N-(2-pyrro]idinoethyl) pyrido[2,3-b]pyrazine3-earboxamide. 3,6-diamin0-N-(4-diinothylan1in0- butyl)pyrido[2,3-b]pyrazine-2- carboxaniide. 3,G-diainiuo-Ncthyl-N Q-dim ethylaininoethyl)pyrido[2,3-b]pyrazine-Z-carboxamide. 3,6-diamino-N-(S-rnethoxypropyl) pyrido[2,3-b1pyrt1zil1e-2-oarb0xam e. 3,G diemino-N-(2-ethylthiocthyl) pyrido{2,3-b]pyrazine-2-carboxamide. 3,6-diarnino-N-(4-butylthiobutyl) pyrido[2,3-b]pyrazine-3-carboxamide. 3,fi-diainino-N-( i-butoxybutyl) pyrido [2,3-b]pyrazine-Zcarboxamide. 3,6-diarninO-N-ethyl-N-(S-isopropoxypropyl)pyrid0[2,3-b]pyrazine-2carboxaniide. 3,6-diamino-N-ethyl (-butylthiobutyl)pyrido[2,3-b]pyrazine-2- carboxamide.

The compounds of this invention exhibit antibacterial,

antiviral, diuretic and anti-inflammatory effects.

All the a wide variety of oral or parenteral unit dosage forms, singly, or in admixture With other active compounds.

The present invention also includes the process of bringing the compounds thereof into a form suitable for therapeutic administration by associating thorn with liquid or solid, pharmaceutically acceptable carriers.

Various changes and modifications of this invention can be made by those skilled in the art to which it relates and to the extent that such variations incorporate the spirit of the invention, they are included in the scope of the claims.

What is claimed is:

1. A compound of the formula:

where Z is selected from the group of R -I I(CH )..-NR1RZ R -1 I c 1 1,) "-0 All:

and

R -IL (CII2)1,SAlk

wherein R is selected from the group of hydrogen and lower alkyl having up to 2 carbon atoms; R and R represent lower alkyl groups having up to 5 carbon atoms, and when taken together to form a closed ring, represent a member of the group consisting of morpholino, piperidino and pyrrolidino; Alk represents a lower alkyl group having up to 4 carbon atoms and the letter 11 is an integer ranging from 2 to 4.

2. 3,6-diamino-N-(3-dimethylaminopropyl)pyrido[2,3- b]pyrazine-Z-carboxsmide.

3. 3,6 dian1ino-N-(Z-diethylaminocthyl)pyrido[2,343] pyrazine-2-carboxamide.

4. 3,6 diamino-N-(2-ethoxyethyl)pyrido[2,3-b1pyrazine-2-carboxamide.

5. 3,6 diamino-N-(Z-hydroxyethyl)pyrido[2,3-b1pyrazine-2-carboxamide.

References Cited by the Examiner Osdene et al.: J. Chem. Soc, London (1955), pages 2027-31.

IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, Examiner. 

1. A COMPOUND OF THE FORMULA: 